In 1998, we were awarded an RO-1 (DA11602) from NIDA to conduct a longitudinal study in HIV-infected persons who have a history of illicit drug use (DU). The major aims of that study were to develop a longitudinal cohort of HIV-infected patients in medical care in order to characterize utilization of the new highly active antiretroviral drug therapies (HAART), and assess the effect of these therapies on HIV disease progression in DUs. We established a comprehensive longitudinal clinic-based cohort of over 4600 HIV infected persons; half of who have a history of DU. Our research suggests that DUs have not received the same level of benefit from HAART as non-DUs. Prior to HAART, there was little difference between DUs and non-DUs in HIV progression. Our research has shown that active DU is a barrier to receiving and adhering to HAART, and achieving effective viral and immunologic improvement on HAART. We hypothesize that the early differences that have emerged between DUs and non-DUs will substantially widen over the next 5 years as HIV resistance to current drugs increases, toxicity limits the use of therapy, and viral hepatitis along with other medical consequences of DU further increase the burden of morbidity. Because of HAART, HIV is now a chronic illness, and DUs have numerous barriers to stable, chronic disease management. We are optimally situated to assess the core factors that impede successful HIV management as the HAART era matures over the next 5 years, and are submitting a new proposal for a competitive continuing RO-I. We propose the following aims, consistent with our overarching goal of improving the outcomes of HIV infection in DUs: 1) Evaluate virologic, immunologic and clinical HIV disease progression for up to 10 years, 2) Assess the impact of viral hepatitis coinfection, 3) Assess other medical consequences of DU including bacterial infection and STDs, 4) Assess adverse effects of HIV therapy. We offer a productive resource to address our aims that is unique in scope and size, cost-efficient in conducting research, highly relevant to the HIV epidemic as it effects DUs, and fully operational from our prior R01. [unreadable] [unreadable]